ORGANIC LETTERS
Short and Efficient Total Synthesis of Fraxinellone Limonoids Using the Stereoselective Oshima−Utimoto Reaction
2005 Vol. 7, No. 24 5465-5468
Ste´phane Trudeau and James P. Morken* Department of Chemistry, The UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
[email protected] Received September 19, 2005
ABSTRACT
The catalytic diastereoselective Oshima−Utimoto reaction was employed for the construction of fraxinellone and related members of this limonoid family of natural products. After formation of the five-membered lactone, a stereoselective aldol reaction and olefin metathesis established the bicyclic ring system in the natural products.
Fraxinellone 1 and isofraxinellone 2 are the simplest examples of degraded limonoids and have been isolated from Rutaceae (Dictamnus albus,1 Dictamnus dasycarpus,2 and Fagaropsis glabra3) and Meliaceae (Melia azedarach4) plants (Scheme 1). While these compounds are known for their
Scheme 1
ichthyotoxic and insect antifeedant activities,5 fraxinellone was also shown to have antiplatelet-aggregation and vascular relaxing activities,6 whereas isofraxinellone has demonstrated antimutagenic activity.7 We viewed these natural products (1) (a) Thomas, H. Ber. Dtsch. Pharm. Ges. 1923, 33, 568. (b) Thomas, H.; Dambergis, C. Arch. Pharm. Chem. 1930, 268, 39. 10.1021/ol0522687 CCC: $30.25 Published on Web 10/27/2005
© 2005 American Chemical Society
as an opportunity to examine the utility of the Pd-catalyzed Oshima-Utimoto reaction for the assembly of sterically encumbered lactone targets.8 This transformation brings about the coupling of simple vinyl ethers and allylic alcohols to afford cyclic five-membered acetals. Recently, we found that (2) (a) Zhao, W.; Wolfender, J.-L.; Hostettmann, K.; Xu, R.; Qin, G. Phytochemistry 1998, 47, 7. (b) Liu, Z. L.; Xu, Y. J.; Wu, J.; Goh, S. H.; Ho, S. H. J. Agric. Food Chem. 2002, 50, 1447. (3) Blaise, A. J.; Winternitz, F. Phytochemistry 1985, 24, 2379. (4) (a) Nakatani, M.; Huang, R. C.; Okamura, H.; Iwagawa, T.; Tadera, K. Phytochemistry 1998, 49, 1773. (b) D’Ambrosio, M.; Guerriero, A. Phytochemistry 2002, 60, 419. (5) Okamura, H.; Yamauchi, K.; Miyawaki, K.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 1997, 38, 263 and references cited therein. (6) (a) Yu, S. M.; Ko, F. N.; Su, M. J.; Wu, T. S.; Wang, M. L.; Huang, T. F.; Teng, C. M. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1992, 345, 349. (b) Wu, T.-S.; Wang, M.-L.; Shyur, H.-J.; Leu, Y.-L.; Chan, Y.-Y.; Teng, C.-M.; Kuo, S.-C. Chin. Pharm. J. 1994, 46, 447. (7) Miyazawa, M.; Shimamura, H.; Nakamura, S. I.; Kameoka, H. J. Agric. Food Chem. 1995, 43, 1428. (8) (a) Fugami, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1987, 28, 809. (b) Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1989, 62, 2050. For a related processes, see: (c) Hafner, W.; Prigge, H.; Smidt, J. Liebigs Ann. Chem. 1966, 109. (d) Larock, R. C.; Lee, N. H. J. Am. Chem. Soc. 1991, 113, 7815. (e) Larock, R. C.; Stinn, D. E. Tetrahedron Lett. 1989, 30, 2767. (f) Kraus, G. A.; Thurston, J. J. Am. Chem. Soc. 1989, 111, 9203.
this transformation can be accomplished in an efficient catalytic and stereoselective fashion with acyclic substrates, and that it can provide a useful tool for the synthesis of interesting natural products, such as (-)-11R,13-dihydroxanthatin.9,10 To further probe the utility of this reaction, we have begun to focus our attention on the synthesis of more challenging targets such as those that bear quaternary centers and considered fraxinellone 1 and isofraxinellone 2, as well as 9R- and 9β-hydroxyfraxinellone (3 and 4)4b and fraxinellonone 52a,4a (Figure 1).
Table 1. Survey of the Catalytic Oshima-Utimoto Reaction with Alcohol 7a
entry
equiv
oxidant
solvent
temp. (°C)
%8
1b 2 3c 4 5d 6 7 8 9 10e
8 2 2 2 2 2 5 8 4 4
none Cu(OAc)2 Cu(OAc)2 BQ BQ/AcOH BQ/AcOH BQ/AcOH BQ/AcOH BQ/AcOH BQ/AcOH
neat CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN neat CH3CN CH3CN
25 55 55 55 55 45 45 45 25 25
77 25 25 39 16 42 48 55 60 55
a Reaction conditions: 10 mol % of Pd(OAc) , 2.5 equiv of Cu(OAc) 2 2 or 3 equiv of BQ, and 1.1 equiv of AcOH (if any); [7] ) 1.0 M, 16 h of b reaction time; BQ ) benzoquinone. 100 mol % of Pd(OAc)2 was used. c 30 mol % of Pd(OAc) was used. d [7] ) 0.2 M in CH CN. e µW ) 300 2 3 W, 2 h of reaction time.
Figure 1.
While previous total syntheses of fraxinellone11,12 and isofraxinellone12 involved formation of the lactone moiety followed by late stage addition of the furan ring, we felt the Oshima-Utimoto reaction would enable an alternate retrosynthetic analysis. In this sense, we anticipated generating a key intermediate lactone, with the furan ring already in place, by executing a catalytic Oshima-Utimoto reaction followed by Jones oxidation. Synthesis of fraxinellone 1 and isofraxinellone 2 began with the preparation of the secondary allylic alcohol 7 by treatment of (E)-2-bromo-2-butene with t-BuLi in THF at -78 °C followed by addition of 3-furaldehyde 6 (Scheme 1). Next, the Oshima-Utimoto reaction was examined using conditions established in our previous report.9 Alcohol 7 was submitted to 10 mol % of Pd(OAc)2, 2.5 equiv of Cu(OAc)2 as the stoichiometric oxidant, and n-butyl vinyl ether in acetonitrile at 55 °C for 15 h. Unfortunately, the reaction was plagued with decomposition of starting material and low yield of desired product (12%). Furthermore, oxidation of the newly formed acetal to the lactone with Jones reagent was also inefficient (20% yield, data not shown). To improve both the Oshima-Utimoto reaction with substrate 7 and the subsequent Jones oxidation, we investigated a series of reaction conditions with tert-butyl vinyl (9) Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3367. (10) Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371. (11) Tokoroyama, T.; Fukuyama, Y.; Kubota, T.; Yokotani, K. J. Chem. Soc., Perkin Trans. 1 1981, 1557. (12) Okamura, H.; Yamauchi, K.; Miyawaki, K.; Iwagawa, T.; Nakatani, M. Tetrahedron Lett. 1997, 38, 263. 5466
ether instead of n-butyl vinyl ether (Table 1). This strategy was adopted since we expected that, under acidic conditions of the Jones oxidation, cleavage of the tert-butyl group might facilitate oxidation. In an initial experiment, stoichiometric palladium(II) acetate was employed in neat tert-butyl vinyl ether at room temperature according to the original conditions set by Oshima and Utimoto, and acetal 8 was generated in 77% yield (entry 1). Using catalytic palladium (10 or 30 mol %) and copper(II) acetate as the reoxidant in acetonitrile at 55 °C, low yields of desired product were obtained (entries 2 and 3). When benzoquinone was used as the oxidant, the yield of product was slightly improved to 39% (entry 3). Addition of acetic acid was found to be inefficient at first (entry 4), but lowering the temperature of reaction and raising the amount of tert-butyl vinyl ether provided a cleaner higher yielding reaction (entries 6-10). The most efficient reaction was observed with 4 equiv of tert-butyl vinyl ether, 10 mol % of Pd(OAc)2, 3 equiv of benzoquinone, and 1.1 equiv of acetic acid in acetonitrile at room temperature. Under these conditions, a 60% yield of desired acetal 8 was obtained after 16 h with >20:1 stereoinduction at the quaternary center and with a 2.6:1 ratio of anomers. It is noteworthy that performing the reaction in a microwave oven at 300 µW accelerated the reaction, giving acetal 8 in 55% yield after 2 h (entry 10). Deprotection and oxidation of tert-butyl acetal 8 with Jones reagent afforded γ-butyrolactone 9 in good yield (Scheme 2). To prepare for construction of the six-membered ring, lactone 9 was deprotonated with LDA and the enolate trapped with 4-penten-2-one (10).13 This aldol reaction furnished alcohol 11 with complete control of the relative configuration Org. Lett., Vol. 7, No. 24, 2005
Scheme 2
Figure 2. X-ray structure of 15.
at the R-carbon but little control of the newly formed hydroxyl stereocenter. While the relative stereochemistry at the newly formed tertiary alcohol was not controlled, both diastereomers could be separated following ring-closing metathesis with Grubbs’ 2nd generation catalyst to provide tricycles 12 and 13 in 95% yield. Additionally, both diastereomers ultimately converge upon the natural product (vide infra). Tricycles 12 and 13 were hydrogenated with 5% palladium on carbon to provide alcohols 14 and 15 in 84 and 91% yield, respectively (Scheme 3). The structure and relative config-
Scheme 3
in a 1:1 ratio of fraxinellone 1 and isofraxinellone 2 in a combined yield of 79%. This difference in product distribution can be explained by the fact that the proton R to the lactone carbonyl in compound 15 is antiperiplanar with respect to the departing oxygen atom and can easily participate in dehydration to afford fraxinellone 1. The methylene protons vicinal to the alcohol can also participate and afford isofraxinellone 2. In contrast, the R-hydrogen in compound 14 is likely orthogonal to the alcohol, and elimination occurs to provide exclusively isofraxinellone 2 by loss of a methylene proton. Finally, migration of the double bond in isofraxinellone can be performed with DBU in benzene to give fraxinellone 1 in 88% yield. To access natural products 3-5, isofraxinellone 2 was treated with m-CPBA in dichloromethane. In this reaction, the electron-rich trisubstituted alkene reacts with the peracid faster than the furan ring to produce a 1:1.6 mixture of epoxides 16 and 17 in 65% yield (Scheme 4).15 While the epoxidation reaction proceeded with poor stereocontrol, both
Scheme 4
uration of alcohol 15 was confirmed by single-crystal X-ray crystallography (Figure 2).14 It is noteworthy that tricycle 12 required 100 psi of hydrogen pressure to perform hydrogenation of the double bond versus 1 atm for compound 13. Completion of the synthesis was accomplished by dehydration of tertiary alcohol with thionyl chloride in pyridine. Alcohol 14 provided exclusively isofraxinellone 2 in 89% yield upon dehydration, while alcohol 15 afforded Org. Lett., Vol. 7, No. 24, 2005
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9R-hydroxyfraxinellone (3) and 9β-hydroxyfraxinellone (4) could be isolated after DBU-induced epoxide opening. Compounds 16 and 17 yielded 3 in 91% yield and 4 in 86% yield, respectively. Fraxinellonone 5 was synthesized by oxidation with TPAP/NMO of either hydroxyfraxinellone 3 or 4 in 86 and 96% yield, respectively. In summary, we have elaborated an efficient route for the synthesis of members of the family of fraxinellone using the catalytic diastereoselective Oshima-Utimoto reaction as the key step. We also surveyed a set of conditions for this key
reaction in order to improve yield and ease of utilization, notably by performing the reaction with milder conditions at room temperature. Current efforts in our laboratories are now directed at the synthesis of other natural product targets. Developments regarding these efforts will be reported in due time. Acknowledgment. This work was supported by the NIH (GM 64451). J.P.M. is a fellow of the Alfred P. Sloan foundation. The authors thank Dr. Peter White of the UNC X-ray analysis facility for assistance with crystallography.
(13) Schmieder-van de Vondervoort, L.; Bouttemy, S.; Padro´n, J. M.; Le Bras, J.; Muzart, J.; Alsters, P. L. Synlett 2002, 243. (14) CCDC 283893 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (15) Similar selectivity in alkenyl furans has been noted: Tanis, S. P.; Herrinton, P. M. J. Org. Chem. 1983, 48, 4572.
Supporting Information Available: Characterization data, spectra, and experimental procedures (31 pages). This material is available free of charge via the Internet at http://pubs.acs.org.
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